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Sudden Cardiac Death and Myocardial Fibrosis, Determined by Autopsy, in Persons with HIV
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June 17 2021 NEJM Zian H. Tseng, M.D., Ellen Moffatt, M.D., Anthony Kim, M.D.,
Eric Vittinghoff, Ph.D., Phil Ursell, M.D., Andrew Connolly, M.D., Ph.D.,
Jeffrey E. Olgin, M.D., Joseph K. Wong, M.D., and Priscilla Y. Hsue, M.D
"In this prospective countywide postmortem investigation of all deaths attributed to out-of-hospital cardiac arrest, we found a higher incidence of presumed sudden cardiac death among persons with known HIV infection than among persons without known HIV infection. Interstitial myocardial fibrosis was also more extensive in HIV-positive persons. One third of apparent sudden cardiac deaths among HIV-positive persons were due to occult drug overdose.
Chronic inflammation and immune activation are present in patients with HIV infection, including those receiving antiretroviral therapy, and inflammatory and coagulation markers are strongly predictive of death,19,20 of illness unrelated to acquired immunodeficiency syndrome,21 and of cardiovascular events.22 Inflammation and immune activation may underlie the increased cardiac fibrosis we observed in the case of sudden deaths in persons with HIV infection. Although myocardial infarction, hypertension, heart failure, and valvular disease are common causes of cardiac fibrosis,23 the proportions of persons with these conditions were similar in cases of sudden death in the group with known HIV infection and the group without known HIV infection, which suggests that other HIV-specific factors contribute to myocardial fibrosis. Furthermore, in persons who were HIV-positive, we observed a greater incidence of interstitial fibrosis, rather than the replacement fibrosis commonly attributed to coronary artery disease. Fibrosis of other organs, including lymph nodes,24,25 adipose tissue,26 and liver,27-29 has been described in the context of HIV."
Abstract
Background
The incidence of sudden cardiac death and sudden death caused by arrhythmia, as determined by autopsy, in persons with human immunodeficiency virus (HIV) infection has not been clearly established.
Methods
Between February 1, 2011, and September 16, 2016, we prospectively identified all new deaths due to out-of-hospital cardiac arrest among persons 18 to 90 years of age, with or without known HIV infection, for comprehensive autopsy and toxicologic and histologic testing. We compared the rates of sudden cardiac death and sudden death caused by arrhythmia between groups.
Results
Of 109 deaths from out-of-hospital cardiac arrest among 610 unexpected deaths in HIV-positive persons, 48 met World Health Organization criteria for presumed sudden cardiac death; of those, fewer than half (22) had an arrhythmic cause. A total of 505 presumed sudden cardiac deaths occurred between February 1, 2011, and March 1, 2014, in persons without known HIV infection.
Observed incidence rates of presumed sudden cardiac death were 53.3 deaths per 100,000 person-years among persons with known HIV infection and 23.7 deaths per 100,000 person-years among persons without known HIV infection (incidence rate ratio, 2.25; 95% confidence interval [CI], 1.37 to 3.70). Observed incidence rates of sudden death caused by arrhythmia were 25.0 and 13.3 deaths per 100,000 person-years, respectively (incidence rate ratio, 1.87; 95% CI, 0.93 to 3.78).
Among all presumed sudden cardiac deaths, death due to occult drug overdose was more common in persons with known HIV infection than in persons without known HIV infection (34% vs. 13%). Persons who were HIV-positive had higher histologic levels of interstitial myocardial fibrosis than persons without known HIV infection.
Conclusions
In this postmortem study, the rates of presumed sudden cardiac death and myocardial fibrosis were higher among HIV-positive persons than among those without known HIV infection. One third of apparent sudden cardiac deaths in HIV-positive persons were due to occult drug overdose. (Supported by the National Heart, Lung, and Blood Institute.)
Human immunodeficiency virus (HIV) infection is associated with increased risk of acute myocardial infarction,1 heart failure,2 and ischemic stroke.3 In 2012, we reported that in San Francisco County, California, the rate of sudden cardiac death, as defined by the World Health Organization (WHO), was 4.5 times as high among HIV-positive persons as among persons without known HIV infection,4 but postmortem data were not available.
We recently reported the results of the Postmortem Systematic Investigation of Sudden Cardiac Death (POST SCD) study, a prospective, countywide postmortem study performed with the use of medical examiner data to ascertain the precise incidence and underlying cause of all deaths due to out-of-hospital cardiac arrest and deaths presumed to be sudden cardiac deaths (as defined by the WHO) in San Francisco County. We found that just over half (55.8%) were sudden deaths from arrhythmia, as determined by autopsy.5 In the current study (HIV POST SCD), we sought to determine the underlying causes of all presumed sudden cardiac deaths and the precise incidence of sudden death caused by arrhythmia in HIV-positive persons and to compare these data with those in the countywide population without known HIV infection. Using postmortem myocardial tissue specimens, we also evaluated the extent of fibrosis to characterize the underlying histologic substrate for sudden death caused by arrhythmia among HIV-positive persons.
Discussion
The HIV POST SCD study was a prospective postmortem evaluation of all incident deaths attributed to out-of-hospital cardiac arrest among HIV-positive persons from February 1, 2011, through September 21, 2016, in San Francisco County. We compared these data with those from the previously reported POST SCD study5 of out-of-hospital cardiac arrests in persons without known HIV infection; autopsy adjudication was used in both studies. In both groups, approximately half the cases of presumed sudden cardiac death were sudden death from arrhythmic causes. However, occult drug overdoses were more than twice as common in the HIV-positive group as in the reference group of persons without known HIV infection. Observed incidence rates of presumed sudden cardiac death were higher among HIV-positive persons. Moreover, among persons with presumed sudden cardiac death and sudden death from arrhythmia, as determined by autopsy, the burden of total and interstitial myocardial fibrosis was higher among HIV-positive persons than among persons in the reference group. We did not find a greater incidence of sudden death from arrhythmia among HIV-positive persons than among persons in the reference group.
In the general population, coronary artery disease has been presumed to be responsible for the majority of sudden cardiac deaths defined by conventional criteria (i.e., without postmortem validation). However, in POST SCD, we reported that as shown by autopsy, coronary artery disease accounted for only one third of all presumed sudden cardiac deaths.5 In the present study, only 23% of presumed sudden cardiac deaths were due to coronary artery disease. Thus, although incidences of acute myocardial infarction and other structural heart disease may be elevated in the context of HIV infection, they do not appear to underlie the higher incidence of sudden deaths that we observed among HIV-positive patients.
In our 2012 study, we reported a mean incidence of sudden cardiac death in HIV-positive persons that was more than 4.5 times as high as that in the general population.4However, it is likely that some sudden cardiac deaths in that study, and indeed in all studies adjudicating sudden cardiac deaths without autopsy, were actually noncardiac deaths, since approximately half of sudden deaths,5 regardless of HIV status, were found to be noncardiac on postmortem investigation. Thus, our study shows the importance of rigorous phenotyping of sudden cardiac death to establish the underlying mechanism. Indeed, we found that the most common cause of presumed sudden cardiac death in HIV-positive persons was actually drug overdose, which highlights the role of noncardiac causes of sudden death in this context.
We found a higher incidence of interstitial cardiac fibrosis among HIV-positive persons than among persons without known HIV infection. Magnetic resonance imaging of the hearts of persons who are HIV-positive (but asymptomatic) shows a higher incidence of myocardial fibrosis, as assessed by late gadolinium enhancement,17 and decreased cardiac function. Late gadolinium enhancement is also higher in persons with nonischemic dilated cardiomyopathy and in survivors of cardiac arrest and is an independent prognostic factor for all-cause mortality beyond ejection fraction.18 Our finding provides histologic confirmation of these radiologic studies and links myocardial fibrosis to sudden death from arrhythmia in persons with HIV infection.
Chronic inflammation and immune activation are present in patients with HIV infection, including those receiving antiretroviral therapy, and inflammatory and coagulation markers are strongly predictive of death,19,20 of illness unrelated to acquired immunodeficiency syndrome,21 and of cardiovascular events.22Inflammation and immune activation may underlie the increased cardiac fibrosis we observed in the case of sudden deaths in persons with HIV infection. Although myocardial infarction, hypertension, heart failure, and valvular disease are common causes of cardiac fibrosis,23 the proportions of persons with these conditions were similar in cases of sudden death in the group with known HIV infection and the group without known HIV infection, which suggests that other HIV-specific factors contribute to myocardial fibrosis. Furthermore, in persons who were HIV-positive, we observed a greater incidence of interstitial fibrosis, rather than the replacement fibrosis commonly attributed to coronary artery disease. Fibrosis of other organs, including lymph nodes,24,25 adipose tissue,26 and liver,27-29 has been described in the context of HIV.
Our study has some important limitations. Although this case series includes all deaths that occurred countywide during the study period, all cases come from a single setting with a distinctive population and disease characteristics that may not apply in other settings. The number of sudden cardiac deaths was small enough that our estimates of incidence rates are not highly precise (as indicated by the wide confidence intervals). As a consequence, we were not able to show a higher incidence rate for sudden death from arrhythmia among HIV-positive persons, although the point estimate for the incidence rate ratio (1.87) suggests the possibility of such an effect. In addition, our findings apply to only the 3.5% of all deaths that met the criteria for presumed sudden cardiac death.
In this prospective countywide postmortem investigation of all deaths attributed to out-of-hospital cardiac arrest, we found a higher incidence of presumed sudden cardiac death among persons with known HIV infection than among persons without known HIV infection. Interstitial myocardial fibrosis was also more extensive in HIV-positive persons. One third of apparent sudden cardiac deaths among HIV-positive persons were due to occult drug overdose.
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